DESCRIPTION (adapted from the applicant's description): The overall objective of the present proposal to elucidate the stress activated signaling mechanisms underlying adaptive response of the heart in the late phase of pharmacologic preconditioning (PC). The central hypothesis is that activation of a specific isoform of protein kinase C, PKCepsilon, is obligatory during the development (on day one) and the manifestation (on day two) of pharmacological preconditioning induced by the adenosine A1 agonist, CCPA, and the opioid agonist, TAN-67, delta-1 receptor during the late phase of PC. Five specific aims are proposed to test the central hypothesis. Specific aim 1 is to conclusively establish the role of PKCepsilon, in CCPA-induced and TAN-67-induced PC. Specific aim 2 will establish a role of the Src family of protein tyrosine kinase (PTKs) in CCPA-induced PC and TAN-67-induced PC. Specific aim three will determine whether Src and/or LCK are obligatory downstream signaling effectors of the PKCepsilon--mediated cardioprotection. Specific aim four will thoroughly characterize signal transduction pathways whereby CCPA-induced PC and TAN-67-induced PC lead to the transcription upregulation of iNOS on day one. Lastly, specific aim five will elucidate signaling mechanisms underlying the posttranslational modulation of iNOS in CCPA-induced and TAN-67-induced PC on day two. These studies will involve multiple approaches including integrative physiology, protein chemistry, molecular biology and transgenic models using both conventional transgenic and gene targeted knockout models in mice.